The goals of this project are to characterize severe chronic infections with Epstein Barr Virus and to characterize multiple aspects of the chronic fatigue syndrome. To date this research project has involved nearly 170 patients. Included are 7 patients who were diagnosed with severe chronic EBV infections on the basis of clinical, historical, molecular and serologic features. We continue to examine immunologic features of patients with severe chronic EBV-associated lymphoprolifer- ation and explore treatments. Interferon proved of little value, but immunosuppressive therapies are being used with good results. Detailed immunologic, neurologic, endocrinologic and psychologic studies are being conducted on selected patients with chronic fatigue. To date we have no consistent laboratory abnormality that permits a clear diagnosis of the chronic fatigue syndrome, however, we have been pursuing the basis and meaning of the group abnormalities in neuropsychiatric, immune and endocrine systems. During the past year we completed a second set of studies of the pituitary-adrenal responsiveness to corticotropin releasing hormone and ACTH and of neuropeptide and catechol levels in spinal fluid. The findings suggest a novel neuroendocrine defect that may indicate deficient central CRH release. Since CRH induces CNS arousal, these neuroendocrine findings suggest a new mechanism whereby the lethargy of Chronic Fatigue Syndrome patients may be explained. During the past year we completed initial controlled immune studies revealing discrete abnormalities in lymphocyte phenotype and in vitro responsiveness to mitogens in patterns suggesting mild immune activation. In the coming year we will focus heavily of these findings.